Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. The acute management of TBI is aimed at preventing secondary neuronal injury, which results from a variety of mechanisms, prominently among them tissue ischemia. Recently, it has become feasible to directly and continuously monitor the partial pressure of oxygen in brain tissue (pBrO2). Several observational studies indicate that episodes of low pBrO2 are common and are associated with a poor outcome, and that medical interventions are effective in improving pBrO2 in clinical practice. However, as there have been no randomized controlled trials carried out to determine whether pBrO2 monitoring results in improved outcome after severe TBI, use of this technology has not so far been widely adopted in neurosurgical ICUs. The proposed study will be the first randomized, controlled clinical trial of pBrO2 monitoring, and is designed to obtain data required for a definitive phase III study, such as efficacy of physiologic maneuvers aimed at treating pBrO2, and feasibility of standardizing a complex intensive care unit management protocol across multiple clinical sites. Patients with severe TBI will be to be monitored with ICP and pBrO2 monitoring, and will be randomized to therapy based on ICP along (control group) or therapy based on ICP in addition to pBrO2 values (treatment group). 182 participants will be enrolled at four clinical sites, the University of Texas Southwestern Medical Center/Parkland Memorial Hospital, the University of Washington/Harborview Medical Center, the University of Miami/Jackson Memorial Hospital, and the University of Pennsylvania/Hospital of the University of Pennsylvania. Functional outcome will be assessed at 6-months after injury. This study has one primary and several secondary hypotheses: (1) Treatment protocol based on pBrO2 monitoring results in reduction of tissue hypoxia. (2). Safety hypotheses: Adverse events associated with pBrO2 monitoring are rare (<3% for combination of infectious, hemorrhagic, or other monitoring-related adverse events) and pBrO2 directed therapy does not result in increased risk of pulmonary or systemic complications (such as acute lung injury/Adult Respiratory Distress Syndrome (ALI/ARDS). (3). Feasibility hypotheses: Episodes of decreased pBrO2 can be identified and treatment protocol instituted comparably across 4 Clinical sites, and protocol violations will be low (<10% and uniform across different clinical sites. (4). Non-futility hypothesis. A relative risk of good outcome measured by the Glasgow Outcome Scale-Extended 6-months after injury of 2.0 is consistent with the results of this phase II study. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost of 45 billion dollars a year in the United States alone. Every year, approximately 1.4 million sustain a TBI, of which 50,000 people die, and another 235,000 are hospitalized and survive the injury. As a result, 80,000-90,000 people experience permanent disability associated with TBI. This results in an enormous psychosocial burden on patients, their families, and society. This project is designed to determine whether a device designed to measure brain tissue oxygenation and thus detect brain ischemia while it is still potentially treatable shows promise in reducing the duration of brain ischemia, and to obtain information required to conduct a definitive clinical trial of efficacy.